| Project/Area Number |
15K10455
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Nara Medical University |
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Principal Investigator |
Honoki Kanya 奈良県立医科大学, 医学部, 教授 (40336863)
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| Co-Investigator(Kenkyū-buntansha) |
藤井 宏真 奈良県立医科大学, 医学部, 学内講師 (00625791)
辻内 俊文 近畿大学, 理工学部, 教授 (10254492)
藤間 保晶 奈良県立医科大学, 医学部, 研究員 (60448777)
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| Project Period (FY) |
2015-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | sarcoma / metabolism / mitochondria / glycolysis / phytochemicals / c-myc / cancer stem cells / phytochmicals / mesenchymal stem cells / osteosarcoma / mitochondria metabolism / phytechemicals / pterostilbene / honokiol / c-myc inhibitor / Pterostilbene / Osteosarcoma / Colon cancer / Cancer stem cells / creatinine kinase / glucose metabolism / PI3k/Akt/mTOR / JAK/STAT |
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| Outline of Final Research Achievements |
Previous research has indicated that pterostilbene (PTE), one of the plant-derived polyphenols, suppressed the proliferative ability of osteosarcoma (OS) cell lines in a dose dependent manner, and the stem cell characteristics such as stem cell markers of Oct, CD44 and NS expression as well as sphere-forming ability. The current research revealed that the mechanism was found to be due to OXPHOS suppression and consequently reduction of ATP production by suppressing complex V activity as a result of an increase in ROS production in mitochondria. In addition, it was shown that tethering of mitochondria and endoplasmic reticulum via PDZD8 is involved in this process. Furthermore, PTE shows a synergistic effect with cMyc inhibitors such as honokiol, JQ1, OTX018, these results suggest that might be novel therapeutic agents against cancer stem cells in OS targeting mitochondrial metabolism.
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| Academic Significance and Societal Importance of the Research Achievements |
骨肉腫患者の予後は、過去四半世紀にわたってブレークスルーがなく、患者の30%近くはいまだ非常に重度の予後、特に転移性疾患に直面している。したがって、新しい治療法が長い間渇望されてきた。本研究の結果は、c-Mycの関与するglycolysisおよびOXPHOSの特徴的な代謝フラックスの調節による「二重代謝阻害」が大きな相乗効果を示し、骨肉腫における幹細胞様細胞集団と一般的な腫瘍細胞集団の両方を標的とする新しい治療戦略となる可能性があることを示唆しており、この難治疾患治療に一筋の光明を与えるものである。
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